By Nancy Volkers
Special To BioWorld Financial Watch
Amid heavy clinical trial activity last month, two companies' products jockeyed for the upper hand in diagnostic imaging for appendicitis, while a maligned pharmaceutical product continued its metamorphosis into a powerful new drug.
That drug is thalidomide, used in the 1950s though never in the U.S. as a treatment for morning sickness. Thalidomide was pulled off the market in 1961, after thousands of women who took it bore children with disfiguring birth defects, such as vestigial limbs and malformed internal organs.
A few years later, a Jerusalem physician gave thalidomide to a leprosy patient afflicted with erythema nodosum leprosum (ENL), which is characterized by painful skin nodules, fever, and other symptoms. The symptoms disappeared. Still used for ENL today, thalidomide is now being tested for at least 30 other indications, including cancers, Crohn's disease, HIV-related wasting (cachexia), and macular degeneration.
Thalidomide apparently inhibits the production of tumor necrosis factor alpha (TNF alpha), a stimulator of inflammation, though its precise mechanisms are unknown. EntreMed, Bristol-Myers Squibb Co. (BMS), and Celgene, Inc., all have trials of thalidomide under way. EntreMed and BMS have a worldwide licensing and research collaboration agreement, under which EntreMed has rights to develop thalidomide for cancer and blindness, and BMS retains rights to thalidomide analogues under development as oral antiangiogenic drugs.
Celgene produces Thalomid, and has been involved with the compound for the past seven years. In 1996, the company submitted a new drug application for ENL, and got final approval last July.
"We have a controlled distribution system so we could monitor the drug on a per patient basis," said Steven Thomas, vice president of pharmaceutical development for Celgene. "Each patient and prescriber fills out a survey to keep us updated."
Because of the risks to fetuses, women of childbearing age who take Thalomid are required to use two forms of birth control, also a requirement of those who take Accutane as a treatment for severe acne.
Celgene research has found that "[Thalomid] is clearly active in a variety of cancers," said Thomas. "What came as a great surprise was also the remarkable activity that the drug apparently has in alleviating many of the symptoms of Crohn's disease," a type of chronic inflammatory bowel disease.
Last month, the company received orphan-drug designation for Thalomid for Crohn's disease. Phase II trials for this indication are ongoing. The National Cancer Institute also recently began trials of the drug for head-and-neck cancer, and for non-small-cell lung cancer. Last year, EntreMed received an orphan drug designation for thalidomide for primary brain tumors.
Thomas lists Thalomid's side effects as somnolence, constipation, numbness and tingling in the extremities, and peripheral neuropathy. "Most side effects can be alleviated through either dose reductions or drug holidays," he said, though peripheral neuropathy can be slow to improve, and in some instances is irreversible.
Through trials, Celgene is "seeking to clarify the mechanism or mechanisms as well as developing analogues and derivatives with increased efficacy," said Thomas. "We want to reduce the dose-limiting problems (the drug can cause sedation) as well as its ability to cause birth defects."
In April, Immunomedics Inc. and Palatin Technologies Inc. announced Phase III results of diagnostic imaging agents for atypical appendicitis. Immunomedics' LeukoScan (sulesomab) and Palatin's LeuTech both use a monoclonal antibody labeled with a technetium isotope. Both are injected and "find" white blood cells, which congregate at sites of infection. The labeled antibodies soon show up on nuclear imaging scans, allowing physicians to see if an appendix is infected or not.
White blood-cell labeling is done currently, but it requires blood drawing, centrifugation, isolation of the blood cells, labeling, and reinjection. The in vivo products could provide simple, less expensive and more accurate ways to diagnose appendicitis, as well as infections such as osteomyelitis and inflammatory bowel disease.
The new products could revolutionize diagnosis, particularly of appendicitis, where current methods still result in an 18 percent rate of unnecessary surgery, said Charles Putnam, chief financial officer of Palatin. "And that's when you have all the symptoms [of appendicitis]," he added. "With equivocal appendicitis, the rate is 30 or 40 percent."
In the recent trials, both companies found their products accurate in diagnosing 91 percent of patients with appendicitis, and ruling out the condition in more than 95 percent of patients who presented with some symptoms.
However, there are differences between LeukoScan and LeuTech.
Cynthia Sullivan, executive director of Immunomedics, said the products are "completely different," partly because LeukoScan uses an antibody fragment, rather than an entire antibody. This reduces the risk of patient reaction, she said.
"There have been zero cases of HAMA [human anti-mouse antibody] detected," she said. "[LeukoScan] has been used in Europe in about 10,000 patients." Last year, LeukoScan was approved in Europe for the diagnosis of osteomyelitis.
Putnam cited a difference in antibody-binding. "LeuTech binds more tightly to the white blood cells than does LeukoScan, providing a clearer scan and easier interpretation," he said. "The strength of the binding is 1,000 to 10,000 times stronger for [LeuTech]."
According to Putnam, this difference means that users of LeukoScan often need computer enhancement to interpret scans, while LeuTech users do not. "Ours is less expensive and less time consuming," he said. LeuTech provides a positive image in about 30 minutes, said Putnam, with 30 percent of the images positive after four minutes.
Sullivan said tighter binding isn't necessary for a diagnostic antibody.
"You're talking about getting the antibody to the site; you don't want it to stay there long, you just want adequate imaging," she said. "The fragment clears from the system very rapidly so you don't have to worry about extended exposure to the patient."
She said LeukoScan's preparation time is about five minutes compared with about 15 or 20 for LeuTech and imaging can begin about 30 minutes after injection, providing LeukoScan users a slight time advantage.
Putnam said Palatin's clinical trial designs are modeled "on the clinical environment. There, either the patient has the disease or they do not. Immunomedics allowed for a third category, equivocal (ambiguous) images. We treated it like a clinician a clinician can't say, 'I don't know.' If we ended up with a bad call, that was the way it was; it affected our results."
Last month, Immunomedics announced a significant cost reduction program to reduce operating expenses by more than $3 million. The company's other lead products include CEA-Cide and LymphoCide, radiolabeled humanized antibodies as therapeutics for various cancers (see BioWorld Today, April 6, 1999). Immunomedics' stock hovered around $2 last week; Palatin's held near $6. Palatin's other lead products include a metallopeptide technology called MIDAS, and a peptide hormone for the treatment of erectile dysfunction called PT-14.
Palatin will meet with the FDA this month to submit a biological license application for LeuTech. Immunomedics submitted a biologics license application for LeukoScan in December 1996, for osteomyelitis and osteomyelitis related to diabetic foot ulcers, as well as acute atypical appendicitis. Sullivan said the application is "under active review." In Europe, LeukoScan is being packaged and distributed by Eli Lilly and Co. *